Neuronal synapses play pivotal roles in neural circuit functions. Abnormal synapse formation leads to numerous developmental diseases of the nervous system with cognitive and behavioral disabilities, including Down Syndrome, Angelman Syndrome, Fragile X Syndrome and Autism Spectrum Disorders. The mechanisms of how synapses form during development are poorly known. Understanding the basic mechanisms of synapse formation will be essential to understand the underpinnings of many birth defects in the nervous system for diagnosis and treatment. Several promising candidates for inducing synapse formation, such as the neuroligins and neurexins, are found not essential for synapse formation. Therefore, the question of synaptogenesis remains unsolved. Wnts have been shown to be able to regulate synapse formation in several embryonic neurons in hippocampus, cerebellum, spinal cord and the neuromuscular junction. Our preliminary results show that Wnt/planar cell polarity (PCP) signaling is required for excitatory synapse formation in dissociated hippocampal neuronal culture and in the neuromuscular junction in vivo. We propose to test the hypothesis that Wnt/PCP signaling is the central pathway, which directly assembles pre- and post-synaptic structures. PUBLIC HEALTH RELEVANCE: Abnormal synapse formation leads to numerous developmental diseases of the nervous system with cognitive and behavioral disabilities, including Down Syndrome, Angelman Syndrome, Fragile X Syndrome and Autism Spectrum Disorders. Understanding the basic mechanisms of synapse formation will be essential to understand the underpinnings of many birth defects in the nervous system for diagnosis and treatment. Several promising candidates for inducing synapse formation, such as the neuroligins and neurexins, are not essential for synapse formation. Therefore, the question of synaptogenesis remains unsolved. We propose to characterize the role and mechanisms of Wnt/PCP signaling in formation of excitatory synapses.